Abstract
Here, we report the design, synthesis, structure-activity relationship studies, antiviral activity, enzyme inhibition, and druggability evaluation of dihydrofuro[3,4-d]pyrimidine derivatives as a potent class of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Compounds 14b (EC50 = 5.79-28.3 nM) and 16c (EC50 = 2.85-18.0 nM) exhibited superior potency against a panel of HIV-1-resistant strains. Especially, for the changeling mutations F227L/V106A and K103N/Y181C, both compounds exhibited remarkably improved activity compared to those of etravirine and rilpivirine. Moreover, 14b and 16c showed moderate RT enzyme inhibition (IC50 = 0.14-0.15 μM), which demonstrated that they acted as HIV-1 NNRTIs. Furthermore, 14b and 16c exhibited favorable pharmacokinetic and safety properties, making them excellent leads for further development.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-HIV Agents / chemical synthesis
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Anti-HIV Agents / metabolism
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Anti-HIV Agents / pharmacokinetics
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Anti-HIV Agents / pharmacology*
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Drug Design
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Female
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Furans / chemical synthesis
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Furans / metabolism
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Furans / pharmacokinetics
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Furans / pharmacology*
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HIV Reverse Transcriptase / antagonists & inhibitors*
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HIV Reverse Transcriptase / genetics
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HIV Reverse Transcriptase / metabolism
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HIV-1 / drug effects*
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HIV-1 / enzymology
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Male
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Mice
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Molecular Docking Simulation
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Molecular Structure
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Mutation
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Protein Binding
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Pyrimidines / chemical synthesis
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Pyrimidines / metabolism
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Reverse Transcriptase Inhibitors / chemical synthesis
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Reverse Transcriptase Inhibitors / metabolism
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Reverse Transcriptase Inhibitors / pharmacokinetics
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Reverse Transcriptase Inhibitors / pharmacology*
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Structure-Activity Relationship
Substances
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Anti-HIV Agents
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Furans
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Pyrimidines
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Reverse Transcriptase Inhibitors
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reverse transcriptase, Human immunodeficiency virus 1
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HIV Reverse Transcriptase